rs143521661

Positions:

• chrX-38322878-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001034853.2(RPGR):​c.222C>T​(p.Ala74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,208,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 251 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., 16 hem., cov: 23)
  • Exomes 𝑓: 0.00061 (0 hom. 235 hem.)
• Consequence: RPGR NM_001034853.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.790

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-38322878-G-A is Benign according to our data. Variant chrX-38322878-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 454515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38322878-G-A is described in Lovd as [Benign]. Variant chrX-38322878-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.79 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.222C>T	p.Ala74=	synonymous_variant	3/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.222C>T	p.Ala74=	synonymous_variant	3/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.000455 AC: 51 AN: 112016 Hom.: 0 Cov.: 23 AF XY: 0.000468 AC XY: 16 AN XY: 34186

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.000665

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000771

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000665 AC: 122 AN: 183463 Hom.: 0 AF XY: 0.000663 AC XY: 45 AN XY: 67915

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000682

Gnomad FIN exome AF: 0.000625

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000615 AC: 674 AN: 1096354 Hom.: 0 Cov.: 28 AF XY: 0.000649 AC XY: 235 AN XY: 361920

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.000341

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000647

Gnomad4 FIN exome AF: 0.000592

Gnomad4 NFE exome AF: 0.000654

Gnomad4 OTH exome AF: 0.000891

GnomAD4 genome AF: 0.000455 AC: 51 AN: 112016 Hom.: 0 Cov.: 23 AF XY: 0.000468 AC XY: 16 AN XY: 34186

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000365

Gnomad4 FIN AF: 0.000665

Gnomad4 NFE AF: 0.000771

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000477 Hom.: 4

Bravo AF: 0.000306

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 20, 2018	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143521661; hg19: chrX-38182131;